Palladium-Catalyzed Carbonylative Synthesis of Benzyl Benzoates Employing Benzyl Formates as Both CO Surrogates and Benzyl Alcohol Sources

Article abstract of DOI:10.1002/ejoc.201900700

An efficient and convenient palladium-catalyzed carbonylation reaction for the synthesis of benzyl benzoates from aryl bromides has been developed. Benzyl formates have been explored as a new type of efficient and useful CO sources and also reaction partners. A wide range of benzyl benzoates was obtained in good to excellent yields.

Full text of DOI:10.1002/ejoc.201900700

A Journal of
Accepted Article
Title: Palladium-Catalyzed Carbonylative Synthesis of Benzyl
Benzoates Employing Benzyl Formates as both CO Surrogates
and Benzyl Alcohol Sources
Authors: ming lai, xinxin qi, and Xiao-Feng Wu
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10.1002/ejoc.201900700
European Journal of Organic Chemistry
COMMUNICATION
Palladium-Catalyzed Carbonylative Synthesis of Benzyl
Benzoates Employing Benzyl Formates as both CO Surrogates
and Benzyl Alcohol Sources
Ming Lai,a Xinxin Qi,a Xiao-Feng Wu*[a,b]
Abstract: An efficient and convenient palladium-catalyzed
carbonylation reaction for the synthesis of benzyl benzoates from
aryl bromides has been developed. Benzyl formates have been
explored as a new type of efficient and useful CO sources and also
reaction partners. A wide range of benzyl benzoates were obtained
in good to excellent yields.
and low yields, long reaction time and so on. Due to the
importance of carbonylation reaction in the preparation of
carbonyl-containing products, and in our continuous efforts
on the development of new CO sources,13 we report here a
new procedure on using benzyl formates as both CO
precursors and benzyl alcohol sources. With palladium as
the catalyst, various benzyl benzoate derivatives were
produced effectively from aryl bromides.
Introduction
Palladium-catalyzed carbonylation reactions have achieved
great progress1 since the pioneering work from Heck and co-
workers in 1974.2 In these reactions, CO gas was used as a
cheap and easily available C1 source, by installing CO into
Results and Discussion
Initially, bromobenzene was used as model substrate,
benzyl formate as both substrate and CO source, with
Pd(OAc)2 as catalyst DPPE as ligand and DBU as base in o-
xylene at 110°C (Table 1, entry 1). To our delight, 17% yield
of the desired product was obtained. Subsequently, various
mono- and bidentate phosphine ligands were studied.
Bidentate phosphine ligands involving DPPB, Xantphos, and
DPPF provided slightly higher yields (Table 1, entries 2-4).
And no more improvements could be observed with
phosphine ligands such as PPh3, PCy3, BuPAd2, P(o-tolyl)3,
and P(p-anisyl)3 (Table 1, entries 5-9). It was noteworthy that
[(t-Bu)3PH]BF4 appeared to be the best ligand, gave the final
product in 90% yield (Table 1, entry 10). No desired benzyl
benzoate product could be obtained with DMAP or K2CO3 as
the base (Table 1, entries 11-12). Furthermore, solvent
screening showed that o-xylene was the optimal solvent for
this transformation (Table 1, entries 13-15).
the parent molecules,
a variety of carbonyl-containing
compounds can be easily prepared. As we known, carbonyl-
containing compounds are very reactive molecules, which
can be used as important synthetic scaffolds in a variety of
chemical
transformations.
Thus,
palladium-catalyzed
carbonylation reactions have gain lots of attentions due to
their widely applications in both academic and industrial
fields. But the uses of gaseous CO, which is toxic, odourless,
and hard to handle, hinder its applications on laboratory
scale. Therefore, much efforts have been put in the
development of CO sources, such as metal carbonyl
complexes,3 paraformaldehyde,4 formates,5 formamide,6
TFBen,7 C6O6,8 CO2,9 formic acid,10 and many others.11
However, most of the known CO surrogates suffer from
particularly required reaction conditions, unneeded residuals,
and some other disadvantages. In this sense, the exploration
of new CO precursors remains highly in demand.
Table 1. Screening of reaction conditions.a
Benzyl benzoates are a class of valuable fine chemical
intermediates, which can be used not only as perfume,
pharmaceutical intermediates, but also in cosmetics, fuel
industry and many other areas.12 There are a lot of synthetic
methods for benzyl benzoates, including esterification of
Entry
1
2
3
4
5
6
7
8
Ligand
DPPE
DPPB
Xantphos
DPPF
PPh3
Base
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DMAP
K2CO3
DBU
DBU
DBU
Solvent
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
Toluene
DMF
Yield (%)b
17
30
37
37
7
24
32
27
25
90
0
benzoic
acid
compounds
with
benzyl
alcohols,
transesterification of benzoates with benzyl alcohols,
Tishchenko reaction, reaction of sodium benzoate with
benzyl chlorides. However, the upper methods have some
drawbacks, such as strict operation conditions, high costs
PCy3
BuPAd2
P(o-tolyl)3
P(p-anisyl)3
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[a]
[b]
M. Lai, Dr. X. Qi, Prof. Dr. X.-F. Wu
9
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha
Campus, Hangzhou 310018, People’s Republic of China
E-mail: xiao-feng.wu@catalysis.de
Homepage: https://www.catalysis.de/mitarbeiter/wu-xiao-feng/
Prof. Dr. X.-F. Wu
10
11
12
13
14
15
0
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-
Einstein-Strasse 29a, 18059 Rostock, Germany
78
85
70
Supporting information for this article is given via a link at the end of
the document.
DMSO
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10.1002/ejoc.201900700
European Journal of Organic Chemistry
COMMUNICATION
aReaction conditions: bromobenzene (1.0 mmol), benzyl
formate (1.5 mmol), Pd(OAc)2 (3 mol%), ligand (3 mol% for
bidentate phosphine ligand, 6 mol% for monodentate
phosphine ligand), base (4.0 mmol), solvent (2.0 mL),
110 °C, 24 h. bYields were determined by GC with
dodecane as an internal standard.
fluoro and chloro moieties were also worked well to give the
final products in high yields (3ka-3la). Aryl bromides with
electron-deficient groups including trifluoromethyl, cynao,
and acetyl able to give the desired benzyl benzoate products
in moderate to good yields as well (3ma-3oa). Remarkably,
the substrates containing 1-biphenyl and 2-naphthalene
moieties were also tolerated well to produce the
corresponding products in good to excellent yields (3pa-3qa).
Moreover, some heterocyclic bromides such as 3-thiophene,
3-pyridine, and 3-quinoline moieties were tested as well; the
desired products were isolated in 75%, 78%, and 71% yields,
respectively (3ra-3ta).
Table 2. Substrate scopes on aryl bromides.a
Furthermore, the substrates scope of benzyl formates
were carried out subsequently (Table 3). Benzyl alcohols
with both electron-rich and electron withdrawing groups
worked very well to afford the desired products in good yields
(3ab-3af).
benzo[d][1,3]dioxol-5-ylmethyl
Finally,
benzhydryl
formate
formate
were
and
also
investigated, and the corresponding products were formed in
high yields as expected (3ag-3ah).
Table 3. Substrate scopes on benzyl formates.a
aReaction conditions: bromobenzene (1.0 mmol), benzyl
formates (1.5 mmol), Pd(OAc)2 (3 mol%), [(t-Bu)3PH]BF4 (6
mol%), DBU (4.0 mmol), xylene (2.0 mL), 110 °C, 24 h,
isolated yield.
aReaction conditions: aryl bromides (1.0 mmol), benzyl
formate (1.5 mmol), Pd(OAc)2 (3 mol%), [(t-Bu)3PH]BF4 (6
mol%), DBU (4.0 mmol), xylene (2.0 mL), 110 °C, 24 h,
isolated yield.
With the optimized reaction conditions in hands, we
went on our investigation of substrate scopes with a variety
of aryl bromides (Table 2). Aryl bromides with electron-
donating groups, such as methyl, ethyl, i-propyl, t-butyl,
methoxy, and trifluoromethoxy groups, provided the target
products in very good yields (3ba-3ja). Substrates bearing
Scheme 1. Control experiments for benzyl formate
decomposition.
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10.1002/ejoc.201900700
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COMMUNICATION
2019, 30, 141-155; for selected examples, see: (c) J. Chen, K. Natte,
X.-F. Wu, J. Organomet. Chem. 2016, 803, 9-12; (d) D.-S. Kim, W.-J.
Park, C.-H. Lee, C.-H. Jun, J. Org. Chem. 2014, 79, 12191-12196; (e)
X.-F. Wu, S. Oschatz, M. Sharif, A. Flader, L. Krey, M. Beller, P. Langer,
Adv. Synth. Catal. 2013, 355, 3581-3585; (f) X.-F. Wu, M. Sharif, K.
Shoaib, H. Neumann, A. Pews-Davtyan, P. Langer, M. Beller, Chem.
Eur. J. 2013, 19, 6230-6233; (g) F. Jafarpour, P. Rashidi-Ranjbar, A. O.
Kashani, Eur. J. Org. Chem. 2011, 2128-2132; (h) P. Nordeman, L. R.
Odell, M. Larhed, J. Org. Chem. 2012, 77, 11393-11398.
Then some control experiments on benzyl formate
decomposition were carried out (Scheme 1). With DBU as
the base, benzyl formate already decomposed at 80 C and
gave the corresponding benzyl alcohol in quantitative yield
together with CO gas (Scheme 1, eq 1). Replace DBU with
NEt3 or in the absence of DBU, benzyl formate stays non-
reacted at the same temperature (Scheme 1, eq 2 and 3).
o
[4]
[5]
(a) T. Morimoto, K. Fuji, K. Tsutsumi, K. Kakiuchi, J. Am. Chem. Soc.
2002, 124, 3806-3807; (b) T. Shibata, N. Toshida, K. Takagi, Org. Lett.
2002, 4, 1619-1621; (c) T. Morimoto, K. Yamasaki, A. Hirano, K.
Tsutsumi, N. Kagawa, K. Kakiuchi, Y. Harada, Y. Fukumoto, N. Chatani,
T. Nishioka, Org. Lett. 2009, 11, 1777-1780; (d) W. Li, X.-F. Wu, J. Org.
Chem. 2014, 79, 10410-10416; (e) K. Natte, A. Dumrath, H. Neumann,
M. Beller, Angew. Chem. Int. Ed. 2014, 53, 10090-10094.
Conclusions
In conclusion, we have developed
a palladium-
catalyzed carbonylation reaction for the synthesis of benzyl
benzoates from aryl bromides. To avoid of the use of toxic
CO gas, benzyl formates was used not only as CO sources,
but also as benzyl alcohol sources for the first time. This
strategy provided an efficient and convenient method for the
synthesis of benzyl benzoate derivatives under mild reaction
condition, and a variety of benzyl benzoates were obtained in
good to excellent yields.
(a) D. Formenti, F. Ferretti, F. Ragaini, ChemCatChem 2018, 10, 148-
152; (b) H. Konishi, H. Nagase, K. Manabe, Chem. Commun. 2015, 51,
1854-1857; (c) Y. Wang, W. Ren, J. Li, H. Wang, Y. Shi, Org. Lett.
2014, 16, 5960-5963; (d) H. Li, H. Neumann, M. Beller, X.-F. Wu,
Angew. Chem. Int. Ed. 2014, 53, 3183-3186; (e) T. Ueda, H. Konishi, K.
Manabe, Angew. Chem. Int. Ed. 2013, 52, 8611-8615; (f) T. Ueda, H.
Konishi, K. Manabe, Org. Lett. 2012, 14, 4722-4725; (g) T. Ueda, H.
Konishi, K. Manabe, Org. Lett. 2012, 14, 5370-5373; (h) T. Ueda, H.
Konishi, K. Manabe, Org. Lett. 2012, 14, 3100-3103; (i) T. Fujihara, T.
Hosoki, Y. Katafuchi, T. Iwai, J. Terao, Y. Tsuji, Chem. Commun. 2012,
48, 8012-8014; (j) Y. Katafuchi, T. Fujihara, T. Iwai, J. Terao, Y. Tsuji,
Adv. Synth. Catal. 2011, 353, 475-482; (k) S. Ko, C. Lee, M.-G. Choi, Y.
Na, S. Chang, J. Org. Chem. 2003, 68, 1607-1610.
Experimental Section
General procedure: under nitrogen, Pd(OAc)2 (3 mol%), [(t-
Bu)3PH]BF4 (tri-tert-butylphosphonium tetrafluoroborate) (6
mol%) was added to a 15 mL tube. After refill the tube with
nitrogen, aryl bromides (1.0 mmol), benzyl formates (1.5
mmol), DBU (4.0 mmol), and o-xylene (2.0 mL) were added
by syringe. Then the tube was closed and the reaction
mixture was stirred at 110 C for 24 h. After the reaction was
completed, the reaction mixture was concentrated by rotary
evaporation. The crude mixture was purified by silica gel
column chromatography (petroleum ether/ethyl acetate =
50/1) to provide the desired pure products.
[6]
[7]
(a) J. Chen, J.-B. Feng, K. Natte, X.-F. Wu, Chem. Eur. J. 2015, 21,
16370-16373; (b) X. Wu, Y. Zhao, H. Ge, J. Am. Chem. Soc. 2015,
137, 4924-4927.
o
(a) J. Ying, H. Wang, X. Qi, J.-B. Peng, X.-F. Wu, Eur. J. Org. Chem.
2018, 688-692; (b) J. Ying, C. Zhou, X.-F. Wu, Org. Biomol. Chem.
2018, 16. 1065-1067; (c) H. Wang, J. Ying, Ming Lai, X. Qi, J.-B. Peng,
X.-F. Wu, Adv. Synth. Catal. 2018, 360, 1693-1703; (d) X. Qi, H.-J. Ai,
N. Zhang, J.-B. Peng, J. Ying, X.-F. Wu, J. Catal. 2018, 362, 74-77; (e)
L.-B. Jiang, X. Qi, X.-F. Wu, Tetrahedron Lett. 2016, 57, 3368-3370.
Z. Wang, Z. Yin, X.-F. Wu, Chem. Commun. 2018, 54, 4798-4801.
(a) X. He, Y. Cao, X.-D. Lang, N. Wang, L.-N. He, ChemSusChem
2018, 11, 3382-3387; (b) X.-D. Lang, F. You, X. He, Y.-C. Yu, L.-N. He,
Green Chem. 2019, 21, 509-514; (c) Q.-W. Song, Z.-H. Zhou, L.-N. He,
Green Chem. 2017, 19, 3707-3728.
[8]
[9]
Acknowledgements
The authors thank the financial supports from NSFC (21602201,
21772177). X.-F. Wu appreciates the generous supports from
Professors Armin Börner and Matthias Beller in LIKAT.
[10] (a) X. Qi, L.-B. Jiang, C.-L. Li, R. Li, X.-F. Wu, Chem. Asian J. 2015, 10,
1870-1873; (b) X. Qi, L.-B. Jiang, H.-P. Li, X.-F. Wu, Chem. Eur. J.
2015, 21, 17650-17656; (c) X. Qi, H.-P. Li, X.-F. Wu, Chem. Asian J.
2016, 11, 2453-2457; (d) X. Qi, C.-L. Li, L.-B. Jiang, W.-Q. Zhang, X.-F.
Wu, Catal, Sci. Technol. 2016, 6, 3099-3107; (e) L.-B. Jiang, R. Li, H.-P.
Li, X. Qi, X.-F. Wu, ChemCatChem 2016, 8, 1788-1791; (f) X. Qi, C.-L.
Li, X.-F. Wu, Chem. Eur. J. 2016, 22, 5835-5838; (g) X. Qi, R. Li, X.-F.
Wu, RSC Adv. 2016, 6, 62810-62813.
Keywords: palladium catalyst • carbonylation • ester synthesis •
CO source • aryl bromides
[1]
For reviews on palladium-catalyzed carbonylations, see: For selected
reviews, see: (a) B. Gabriele, R. Mancuso, G. Salerno, Eur. J. Org.
Chem. 2012, 6825-6839; (b) X. F. Wu, H. Neumann, M. Beller, Chem.
Rev. 2013, 113, 1-35; (c) S. Sumino, A. Fusano, T. Fukuyama, I. Ryu,
Acc. Chem. Res. 2014, 47, 1563-1574; (d) J.-B. Peng, X. Qi, X.-F. Wu,
Synlett 2017, 28, 175-194; (e) X.-F. Wu, RSC Adv. 2016, 6, 83831-
83837; (f) J.-B. Peng, X. Qi, X.-F. Wu, ChemSusChem 2016, 9, 2279-
2283; (g) Y. Bai, D. C. Davis, M. Dai, J. Org. Chem. 2017, 82, 2319-
2328; (h) T. Morimoto, K. Kakiuchi, Angew. Chem. Int. Ed. 2004, 43,
5580-5588.
[11] (a) J. J. Verendel, M. Nordlund, P. G. Andersson, ChemSusChem,
2013, 6, 426-429; (b) S. H. Christensen, E. P. K. Olsen, J. Rosenbaum,
R. Madsen, Org. Biomol. Chem. 2015, 13, 938-945; (c) D. S. Laitar, P.
Müller, J. P. Sadighi, J. Am. Chem. Soc. 2005, 127, 17196-17197; (d) C.
Kleeberg, M. S. Cheung, Z. Lin, T. B. Marder, J. Am. Chem. Soc. 2011,
133, 19060-19063; (e) H. Zhao, H. Du, X. Yuan, T. Wang, W. Han,
Green Chem. 2016, 18, 5782-5787; (f) S. Korsager, R. H. Taaning, T.
Skrydstrup, J. Am. Chem. Soc. 2013, 135, 2891-2894; (g) M. N.
Burhardt, R. H. Taaning, T. Skrydstrup, Org. Lett. 2013, 15, 948-951;
(h) R. F. Cunico, B. C. Maity, Org. Lett. 2003, 5, 4947-4949; (j) M. L. N.
Rao, V. Venkatesh, P. Dasgupta, Tetrahedron Lett. 2010, 51, 4975-
4980; (k) S. V. F. Hansen, T. Ulven, Org. Lett. 2015, 17, 2832-2835; (l)
M. Markovič, P. Lopatka, P. Koóš, T. Gracza, Org. Lett. 2015, 17, 5618-
5621; (m) S. D. Friis, A. T. Lindhardt, T. Skrydstrup, Acc. Chem. Res.
2016, 49, 594-605.
[2]
[3]
(a) A. Schoenberg, I. Bartoletti, R. F. Heck, J. Org. Chem. 1974, 39,
3318-3326; (b) A. Schoenberg, R. F. Heck, J. Org. Chem. 1974, 39,
3327-3331; (c) A. Schoenberg, R. F. Heck, J. Am. Chem. Soc. 1974, 96,
7761-7764.
For two excellent reviews, see: (a) L. R. Odell, F. Russo, M. Larhed,
Synlett 2012, 685-698; (b) L. Åkerbladh, L. R. Odell, M. Larhed, Synlett
This article is protected by copyright. All rights reserved.

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[12] B. Liu, F. Lu, B. F. Shi, ACS Catal. 2015, 5, 1863-1881.
1437; (e) F.-P. Wu, J.-B. Peng, X. Qi, X.-F. Wu, J. Org. Chem. 2017, 82,
9710-9714; (f) F.-P. Wu, J.-B. Peng, L.-Y. Fu, X. Qi, X.-F. Wu, Org. Lett.
2017, 19, 5474-5477; (g) F.-P. Wu, J.-B. Peng, X. Qi, X.-F. Wu,
ChemCatChem 2018, 10, 173-177; (h) B. Chen, J.-B. Peng, J. Ying, X.
Qi, X.-F. Wu, Adv. Synth. Catal. 2018, 360, 2820-2824.
[13] (a) H.-P. Li, H.-J. Ai, X. Qi, J.-B. Peng, X.-F. Wu, Org. Biomol. Chem.
2017, 15, 1343-1345; (b) F.-P. Wu, J.-B. Peng, L.-S. Meng, X. Qi, X.-F.
Wu, ChemCatChem 2017, 9, 3121-3124; (c) F.-P. Wu, J.-B. Peng, X.
Qi, X.-F. Wu, Catal, Sci. Technol. 2017, 7, 4924-4928; (d) J.-B. Peng,
F.-P. Wu, C.-L. Li, X. Qi, X.-F. Wu, Eur. J. Org. Chem. 2017, 1434-
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COMMUNICATION
COMMUNICATION
Carbonylation
Ming Lai, Xinxin Qi, Xiao-Feng Wu*
Page No. – Page No.
Palladium-Catalyzed Carbonylative
Synthesis of Benzyl Benzoates
Employing Benzyl Formates as both
CO Surrogates and Benzyl Alcohol
Sources
An efficient and convenient palladium-catalyzed carbonylation reaction for the
synthesis of benzyl benzoates from aryl bromides has been developed. Benzyl
formates have been explored as a new type of efficient and useful CO sources and
also reaction partners. A wide range of benzyl benzoates were obtained in good to
excellent yields.
This article is protected by copyright. All rights reserved.